Lissencephaly (smooth cortex) is caused by abnormal cortical neuronal migration and leads to severe mental retardation and seizures. Cajal-Retzius (CR) cells are early born cortical neurons that have critical functions in regulating the final laminar location of migrating cortical neurons. However, little is known about the developmental program of CR cells. This proposal will investigate the hypothesis that SDF1-CXCR4- mediated chemoattraction and slits-robos-mediated chemorepulsion regulate the migration of cortical hem (CH)-derived CR cells. To test this hypothesis, the CH marker gene Frizzled 10 promoter drived lacz (frzlO- lacz) transgenic mice, Frz10-lacz-CXCR4 null mice and Frz10-lacz-slit1/2 null mice will be generated and the migration of CH-derived CR cells in these mice will be analyzed in vitro and in vivo. For in vitro assays, brain slice and CH explant collagen cultures will be stained with lacz antibody to examine whether Frz10-lacz- CXCR4 null mice and Frz10-lacz-slit1/2 null mice show any CR cell migration defects. If so, overexpression experiments with electroporation of SDF1 and slits in vitro and in vivo will be performed. The results from these experiments will provide some insight for developing novel therapeutic targets in Lissencephaly.